Abstract. Collections of human sera from malaria-endemic areas would be valuable for identifying and characterizing antigens as malaria vaccine candidates if the contributing serum donors' ability to resist infection were fully characterized. We prepared such a serum collection from 26 apparently immune Nigerian adults who failed to develop patent parasitemia for at least 20 weeks following a documented increase in antibodies to the circumsporozoite protein (CSP) from Plasmodium falciparum. Volunteers were evaluated five times per week for malaria symptoms and bimonthly for parasites by examining thick blood smears. The incidence rate over 13 months for the cohort was 42% (47 malaria-confirmed volunteers) and the risk of infection was 1.3 infections/year. Responses to CSP did not correlate with protection. Because antibody responses to antigens other than CSP may be associated with protection, the sera from these immune individuals may be useful for identifying and characterizing other potential malaria vaccine candidates.Malaria, particularly that caused by Plasmodium falciparum, remains one of the most serious diseases in the world, endangering infant and early childhood development in many tropical regions lacking the resources to implement thorough and widespread control programs. With the emergence of insecticide-resistant Anopheles mosquitoes and of drug-resistant P. falciparum, the prospect of human survival in malaria-endemic areas has become increasingly grave. Hope for successful control of malaria seems to lie in a concerted multi-pronged approach that includes environmental and continued vector control methods, combined with an appropriate use of anti-malarial drugs and continued efforts towards the development of malaria vaccines.Antigens from several developmental stages of P. falciparum are being evaluated for inclusion in a malaria vaccine, 1-11 with circumsporozoite protein (CSP) from the sporozoite stage and merozoite surface protein-1 (MSP-1) from the erythrocytic stage 12-17 receiving the most attention. Antibody responses to the central repeat region of the CSP have been studied in several malaria-endemic areas. Some investigators concluded that anti-CSP antibodies were protective, 18-20 while others did not. [21][22][23] Adult sera from malaria-endemic areas have been used in a number of clinical [24][25][26] studies to show that antibody can passively transfer protection against erythrocytic stage infections. Such sera have also found application in defining parasite antigens for inclusion in a malaria vaccine. 27-30 Sera such as these should be most valuable for the purpose of antigen discovery and characterization if the relative immune status of the donors were known.In the absence of detectable erythrocytic stage parasites, one method for assessing if a person living in an area of endemic malaria has been exposed to P. falciparum sporozoites is to measure boosting of the levels of the anti-CSP antibodies. Gordon and others 31 assumed that a two-fold or greater increase in antibody leve...